Nonsurgical Management Peyronie’s Disease
There are several options for the nonsurgical management of the patient with PD, including systemic medical therapy, topical and intralesional injection therapy, extracorporeal shockwave therapy, and iontophoresis. Many of these therapies have not undergone rigorous evaluation in controlled clinical trials; most of the relevant studies are retrospective and provide little more than anecdotal evidence to support the use of the agents studied.
Medical Pharmacotherapy
One of the most commonly prescribed medical treatments for PD is tocopherol (vitamin E). Tocopherol serves as an antioxidant and oxygen free-radical scavenger. It is in this role that tocopherol is purported to be useful in the treatment of PD by decreasing rates of fibrosis. Although in-vitro data have shown that oxygen free radicals can produce cavernosal fibrosis, no in-vivo evidence supports this finding. In fact, studies have failed to show any significant benefit.
One randomized controlled trial in 40 patients with PD found a 35% improvement in pain with tocopherol, but there was no improvement in curvature or plaque size. Vitamin E may serve to improve the psychological impact of PD through the placebo effect. Side effects are relatively rare and mild and include nausea, vomiting, diarrhea, and blurred vision.
Para-aminobenzoate (PABA) was introduced as a medical therapy for PD after in-vitro data demonstrated a decrease in collagen production when combined with cultured fibroblasts. It is postulated that PABA works by enhancing antifibrotic properties of tissue, including decreasing tissue levels of serotonin. Again, randomized clinical data are limited.
However, one randomized placebo-controlled trial comparing PABA and placebo over 1 year demonstrated a 74% beneficial response for the treatment group compared with a 50% response in the placebo group. A beneficial response was defined as regression in plaque size and/or a reduction in penile curvature. Most of the improvement was seen in stabilization or reduction in plaque size; therefore, the authors recommended PABA as a means to limit progression of the disease. PABA is an expensive medication and is taken 4 times daily. The main side effects are gastrointestinal and include nausea, vomiting, and diarrhea.
Another agent used to treat PD is colchicine. It is thought to decrease phagocytosis of inflammatory cells, which lead to decreased collagen production and increased collagenase activity. Several studies have evaluated the efficacy of colchicine in patients with PD. One study examined 60 men presenting during the acute phase of PD.
At a mean follow-up of 11 months, the investigators noted a lessening of pain in 95% of men, with 30% of subjects reporting improvements in curvature and 22% reporting worsening of curvature. The authors proposed that patients presenting early in the disease course with less than 30° of curvature would benefit most from this agent. In another trial, 84 men with PD were randomly assigned to receive colchicine or placebo.
These patients were evaluated with penile duplex Doppler studies as well as validated questionnaires. The mean duration of symptoms was 15 months. At follow-up, there were no significant differences in pain, plaque size, or curvature between the 2 treatment groups. It is possible that colchicine may be beneficial for patients presenting only in the acute phase of the disease, as in-vitro data does show evidence of decreased collagen production if treated early in the disease process. Side effects of colchicine include nausea, vomiting, and diarrhea.
Two other oral therapies with promising in-vitro data include L-arginine and pentoxifylline. L-arginine is converted to nitric oxide by nitric oxide synthase and has been shown to reduce plaque size in a rat model. Additionally, pentoxifylline is a nonspecific scavenger of reactive oxygen species (ROS) and may also decrease plaque size. No human trials — only anecdotal reports — have been published to date using these 2 medications, but these reports do suggest a possible treatment benefit.
Intralesional Injection Therapy
Intralesional therapies, involving the injection of steroids into penile plaques, have been in use since the 1950s. The theory behind this approach was that the anti-inflammatory effects of corticosteroids would prove beneficial; results of studies have been disappointing, however. Patients treated with intralesional injections of corticosteroids have shown little benefit, especially when weighed against the side effects of tissue atrophy and immune suppression. Other intralesional therapies, however, have shown promise and may serve as a minimally invasive treatment option for patients.
Collagenases, also known as specific matrix metalloproteinases (MMPs)-1, -8, and -13, are a family of enzymes capable of degrading collagen. Gelbard and colleagues[25] were the first to study collagenases in the treatment of PD. In-vitro data showed a significant reduction in penile plaque and dispersion of collagen bundles in human tissue treated with collagenases.
On the basis of these in-vitro data, a study was undertaken in which 31 men with PD were injected with purified clostridial collagenase. An objective improvement was noted in 65% of patients. Subsequently, a randomized placebo-controlled trial was instituted involving 49 men who were stratified into 1 of 3 groups: curvature < 30° or plaque size < 2 cm; curvature 30°-60° or plaque size 2-4 cm; or curvature > 60° or plaque size > 4 cm.
After 3 months of treatment, improvement was found in all patients in group 1, 36% of patients in group 2, and 13% of patients in group 3. A more recent prospective nonrandomized study evaluated 25 men with PD treated with intralesional therapy with purified clostridial collagenase. Significant improvements in curvature and plaque size were found at 3 and 6 months. A double-blinded, randomized study using this agent is currently under way.
Verapamil is a calcium channel antagonist that has been used for intralesional as well as transdermal treatment of PD. The rationale for its use is based on in-vitro data demonstrating that the transport of various extracellular matrix molecules (including collagen and fibronectin) is a calcium-dependent process. In addition, verapamil has also been shown to increase collagenase activity, affect cytokine expression, and decrease fibroblast proliferation in PD plaques.
The use of intralesional verapamil was popularized by Levine and coworkers, whose nonrandomized study of men with PD demonstrated improvement in penile narrowing, curvature, and plaque volume. The same investigators also followed 156 men with PD in a nonrandomized study for a mean of 30 months and found significant improvements in pain and curvature in the majority of men and only 8% of men reported worsening of their curvature.
The only randomized placebo-controlled study examining verapamil involved 14 men with PD. Results showed significant improvements in plaque volume, penile narrowing, pain, and erectile function, but overall penile curvature was not statistically different from placebo. Verapamil is generally administered in 10-mg doses every 2 weeks for a total of 12 treatment sessions. If no improvement is seen after 6 treatments, the dose may be increased to 20 mg or alternate therapies may be initiated. Additional randomized studies are needed to fully elucidate the effect of intralesional verapamil, but the initial prospective results show promise.
Interferons have been used for the treatment of PD since these molecules were found to inhibit fibroblast activity and collagen production in cultured fibroblasts from PD plaques. Several prospective studies and anecdotal reports demonstrated improvements in curvature and pain with interferon treatment (most commonly, IFN-alfa 2b). A crossover study was performed in which 7 of 21 men underwent injection with placebo for 6 weeks followed by a 1-month washout period and then a treatment course of IFN-alfa 2b.
The remaining men underwent injection with interferon only. Results were evaluated using the penile duplex Doppler ultrasound and the IIEF questionnaire. Two thirds of men in this study exhibited objective improvement in curvature. Improvements in plaque size and erectile function were seen in 71% of men. Statistically significant improvements were observed in penile pain and curvature. A follow-up study also revealed significant improvements in penile hemodynamics. R
Recently, a multicenter randomized placebo-controlled trial was conducted to compare the efficacy of intralesional IFN-alfa 2b vs saline placebo injections.[36] Fifty-five of the 117 men in this trial were randomized to receive 5 x 106 units IFN-alfa 2b every 2 weeks for 6 weeks. These men were then evaluated by penile duplex Doppler ultrasound and IIEF questionnaire. Patients who received active treatment experienced significant reductions in penile curvature (decrease of 13.5° for IFN vs 4.5° for placebo), plaque size, and pain, as well as improvements in penile blood flow.
There were no significant differences between the 2 groups in IIEF scores. Treatment with interferon is associated with myalgias, arthralgias, fever, and flu-like symptoms. These symptoms may last for 24 hours. Pretreatment with nonsteroidal anti-inflammatory drugs prior to injection usually alleviates these symptoms. Future studies regarding the use of interferon will hopefully elucidate the proper dosing regimen as well as length of treatment for optimal results.
Other Nonsurgical Management Options
There are other nonsurgical therapies for PD besides medical therapy and intralesional injections. One potential treatment option that has been studied is penile shockwave therapy. The theory behind the treatment is that initiating an inflammatory reaction through direct damage to the plaque will result in plaque resorption. However, multiple randomized studies designed to evaluate the efficacy of shockwave therapy have failed to show any improvements in curvature or plaque size.
Other therapies include iontophoresis, which involves the use of electric currents to improve transdermal drug penetration. Typically this treatment is used in conjunction with topical verapamil.[38] Small nonrandomized studies have shown some improvement. However, the results are still inferior to those of intralesional injection therapy. Further studies are currently under way. An intriguing treatment option that has been studied in recent trials is the use of penile traction devices. These extenders are typically used in conjunction with intralesional therapy.
A small pilot study (N = 10) conducted by Levine and colleagues evaluated the use of a penile traction device and found a 33% reduction in curvature and increases in penile length between 0.5 and 2 cm. These devices, which are typically worn for a total of 4-8 hours per day, are cumbersome for some patients, but initial data appear encouraging. Further studies are certainly needed to evaluate this treatment option.
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